1. Field of the invention
The present invention relates to an apparatus which can be used in research and has a reaction vessel, preferably a multiplicity of reaction vessels combined in a block, for carrying out chemical, biochemical or physical experiments in parallel and/or in series. In many experiments, it is necessary for the reaction vessel to be temperature-controlled, e.g. in the range between xe2x88x9270xc2x0 C. and +200xc2x0 C., with a simultaneous shaking movement and simultaneous metering into a closed reaction vessel. The equipment thus has to meet particular requirements.
2. Prior art
For example in chemical research in the pharmaceutical industry or in university research, it is increasingly important to discover, and then to test, a large number of potential active ingredients or combinations as quickly as possible. Some of the chemical research thus currently deals with combinatorial chemistry, parallel synthesis and high-speed chemistry. Of prime importance here is the possibility of being able to make wide use of known or novel chemical reaction types in parallel with minimal adaptation.
Various apparatuses with reaction vessels which are arranged in parallel, can be temperature-controlled and are intended for carrying out a multiplicity of experiments in parallel have thus been provided. In the simplest of these, use was made of open oil baths in which a block of the reaction vessels is fitted such that it can be shaken. The gravest disadvantage of such constructions is the narrowly restricted temperature range as a result of the open temperature-controlled bath in relation to a closed circuit. A further essential disadvantage is that it is not possible, during the shaking movement, to meter, for example, the solution of a reagent into the closed reaction vessels using an addition apparatus, e.g. a needle. Further temperature-controllable apparatuses provided are merely suitable for specific applications, for the most part of complicated construction, excessively large, not particularly user-friendly or barely allow any automation of individual process steps.
DE-A-32 20 879 discloses an apparatus for retaining reaction vessels which can be temperature-controlled and shaken by means of a shaking arrangement. The reaction vessels are retained in each case by means of an elastic coupling at the top and are mounted in recesses of elastic rests at the bottom. For the temperature control of the reaction vessels, there is arranged above the elastic rests, as a resistance heating means, a receiving body with through-passage bores through which the bottom ends of the reaction vessels project. The temperature control of reaction vessels via the resistance heating means and air located therebetween is still capable of improvement in terms of efficiency.
DE-C42 14 866 discloses a further apparatus for retaining test tubes which can be temperature controlled and shaken by means of a vibrating plate. Connected to the vibrating plate is a sample holder which, on its top side, is provided with pads which are made of elastic material and in which the bottom ends of the test tubes engage. A heating plate through which air can flow is arranged between the vibrating plate and sample carrier. In order that the hot air for heating the test tubes does not escape outward, said test tubes have to be enclosed by a casing.
Bohdan Europe, France, have brought an improved apparatus onto the market under the designation RAM Synthesizer BHD 1524. This apparatus comprises a heat-conducting temperature-control block with a multiplicity of depressions. A central inlet is provided in order to supply the temperature-control block with a liquid heat-transfer medium. The reaction vessels, which are screwed on a cavity plate and closed by septa, are introduced into the depressions, the top cavity plate with the screwed-on reaction vessels being rigidly fastened on the temperature-control block. The heating temperature control of the reaction vessels takes place in this case by energy being fed from the heat-transfer medium to the temperature-control block, in the direction of the shell of the reaction vessel. During cooling temperature control, the drop in temperature between the shell of the reaction vessel and the heat-transfer medium, via the heat-dissipating temperature-control block, causes a transfer of energy from the reaction vessel in the direction of the heat-transfer medium. The entire reaction block is positioned on a shaking arrangement and can thus be shaken and temperature-controlled at the same time.
The disadvantage with the RAM Synthesizer BHD 1524 apparatus is that during the shaking operationxe2x80x94with possible temperature control at the same timexe2x80x94the individual reaction vessel cannot be penetrated by a needle-like sampler, which is typically guided by a robot arm, in order for substances to be added or removed. However, it is precisely during the addition of substances that the operation of shaking the reaction vessel is often essential. The reaction vessel must necessarily be closed by a septum, with the result that a sampler introduced into the reaction vessel would have to be moved adequately at the frequency and amplitude of the shaking movement of the reaction vessel. With a, for example, conventional deflection of the reaction vessel of 10 mm with a rotation of 1000 revolutions/minute, the operation of moving the sampler along synchronously is ruled out in practice and is extremely disadvantageous (centrifugal forces). The above described apparatus, however, also has other disadvantages. During the shaking operation, it is necessary for the reaction block to be moved as a whole, which requires very stable equipment (vibration) and a powerful drive. For the temperature transfer from the liquid heat-transfer medium and the wall of the reaction vessel, the temperature-control block is interposed as a delaying and energy-absorbing component. Even in the case of very precise depressions and, at the same time, very precise reactors, a layer of air which, although minimal, has a pronounced insulating effect is produced between the temperature-control block and reactor.
In view of the disadvantages presented, the object of the invention is to provide an apparatus where an individual reaction vessel and/or a block of reaction vessels are temperature-controlled as far as possible without any delay and with low losses. During the temperature control, it has to be possible for the reaction vessels to be shaken at the required intensity, in which case the substance surrounding the reaction vessels is to be moved as little as possible. Finally, it has to be possible, at the same time as the temperature-control and shaking operations, to use a sampler to meter substances into the reaction vessels, which may possibly be closed by a septum, or to take samples from the reaction vessels.
The essential features of the invention may be summarized as follows:
The apparatus for retaining a reaction vessel which can be temperature-controlled and shaken is preferably designed as a block with a multiplicity of combined reaction vessels. A flow channel for supplying a liquid temperature-control medium is routed up to reaction vessels and the apparatus has a shaking arrangement for moving the reaction vessels. The reaction vessels are retained in each case by means of an elastic coupling at the top of their neck sections and are supported in a sealed manner in elastic receptacles beneath their neck sections such that it is not possible for any liquid temperature-control medium supplied via the flow channel to escape. The shaking arrangement preferably acts on the elastic means which provide a supporting function beneath the reaction vessels.
The elastic coupling has a basically sleeve-like configuration with an axial through-passage. Its top end may be provided with an external thread for fastening on a carrier. The bottom end of the coupling advantageously has a fixing region and, right at the bottom, a standard ground joint. A folding bellows is located between the top and the bottom ends. The bottom end is inserted at least in part, preferably by way of the standard ground joint, into the inlet opening of the neck section of the reaction vessel. A number of embodiments have been developed for the elastic receptacles for providing bottom support for the reaction vessels.
The elastic receptacles supporting the reaction vessels beneath their neck sections is formed by a block with a multiplicity of cylindrical, elastic walls which extend upward from the top side of said block. These walls constitute receiving stubs which each have an insertion opening which continues into the block as a hole. Each hole is intended for receiving the base section of a reaction vessel and each associated elastic wall is intended for engaging radially part of the way around said reaction vessel. The flow channel, for supplying the temperature-control medium, is routed to each hole, said temperature-control medium flowing out of the flow channel and around the respective reaction vessel.
The elastic receptacles means supporting the reaction vessels beneath their neck sections is formed by a block with a multiplicity of cylindrical, elastic walls which extend upward from the top side of said block and extend downward from the underside of said block. The walls on the top side and the underside constitute mutually aligned receiving stubs and each have a vertical through-passage in order to receive in each case the central section of a reaction vessel therein. The base sections of the reaction vessels project out of the bottom elastic walls, while the neck sections project out of the top elastic walls. Each elastic wall is intended for engaging radially part of the way around the inserted reaction vessel. The flow channel, for supplying the temperature-control medium, is routed to each vertical through-passage, said temperature-control medium flowing out of the flow channel and around the respective reaction vessel.
Both in the case of the first embodiment and in the case of the second embodiment, the flow channel begins at least one inlet on the block and ends at least one outlet. The flow channel continues from one hole to the adjacent hole or from one vertical through-passage to the adjacent vertical through-passage. The entire block advantageously consists of elastic material.
The elastic receptacles supporting the reaction vessels beneath their neck sections is formed by a block with a multiplicity of cylindrical, elastic couplings which extend upward from the top side of said block and receive at least the base section of the respective reaction vessel and engage radially around the same. The flow channel, for supplying the temperature-control medium, which flows around the respective reaction vessel, is routed into the interior of each coupling.
The elastic coupling has a basically sleeve-like configuration and an axial through-passage. A top socket element on the coupling has a sealing surface for engaging around the reaction vessel in a sealed manner, said reaction vessel having a sealing surface which is complementary. The coupling is terminated at the bottom by an attachment flange for fastening on the top side of the block. A folding bellows is located between the top socket element and the bottom attachment flange. In order to secure the retained reaction vessel and to produce a contact pressure between the sealing surfaces located one upon the other, a collar is provided on the reaction vessel, from which a clamp engages over to the socket element.
The flow channel, for supplying the temperature-control medium, emerges directly in the region of the elastic coupling fastened on the top side and continues, as a discharging flow channel, into the interior of the adjacent coupling. In the adjacent coupling, the discharging flow channel coming from the previous coupling fulfills a supply function.
This embodiment is similar to the third embodiment, but a flow tube which projects into the interior of the coupling and is intended for supplying the temperature-control medium is connected to the flow channel in the block. The temperature-control medium is discharged via an outgoing flow channel which opens out in the region of the elastic coupling fastened on the top side.
The invention, now, makes available a perfected apparatus which makes it possible for the reaction vessels retained therein to be temperature-controlled and shaken at the same time and, during these operations, for the reaction vessels to be penetrated by a removal and/or addition element for sample-taking or metering-in purposes. The removal and/or addition element may be guided by a robot. By virtue of the circulation of the temperature-control medium in a closed circuit, the reaction vessels can be temperature-controlled over a large temperature range, to be precise each reaction vessel in parallel or all reaction vessels in series.